Kaposi's Sarcoma (KS) is the most common oral malignancy of AIDS patients and causes significant morbidity and mortality. The main tumor cell of KS is the spindle cell, a cell of endothelial origin. The etiologic agent of KS is Kaposi's Sarcoma-associated herpesvirus (KSHV) and is found in the spindle cells of all KS tumors. This proposal seeks to understand how latent KSHV activates endothelial cells through angiogenic and lymphangiogenic pathways to induce KS tumors in the oral environment. Latent KSHV infection increases the expression of both angiogenic and lymphangiogenic receptors in endothelial cells and this proposal will examine how KSHV activates both angiogenic and lymphangiogenic phenotypes. Integrins play a critical role in angiogenesis and in the first Aim, the role of KSHV induced integrins in the induction of angiogenic phenotypes during latency will be examined. A number of integrin inhibitors are in clinical trials and these studies will determine the potential of these inhibitors for treatment of KS tumors. KSHV also induces the differentiation of blood endothelial cells to lymphatic endothelial cells. Spindle cells in the KS tumor express markers of lymphatic endothelium and in particular VEGF receptor3 a key receptor in the induction of lymphangiogenesis. In Aim 2 the mechanism of KSHV induced blood to lymphatic endothelial cell differentiation will be examined and new factors involved in this process will be analyzed to determine the mechanism of KSHV induced reprogramming to lymphatic endothelium. Finally, in Aim 3 we will determine if the integrins described in Aim 1 are highly expressed in oral KS tumors. The expression of previously undefined cellular factors critical for KSHV induced blood to lymphatic endothelial cell differentiation will also be examined in KS tissue. KSHV induces both angiogenic and lymphangiogenic receptors and phenotypes and a better understanding of how KSHV activates endothelial cells through these pathways will lead to new and better treatment options for KSHV and KS tumors.